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Category: genetics

EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer

Oral squamous cell carcinoma (OSCC) is a painful disease that severely impairs eating, drinking, and talking (1–5). Patients with OSCC are less opioid responsive and develop opioid tolerance quicker than patients with other chronic pain conditions (6, 7). Escalating doses of opioids are required as tolerance develops, causing not only severe adverse effects (6) such as addiction but also prolonged hospitalizations and increased readmission rate in patients (8). The mechanisms underlying oral cancer pain and opioid tolerance are not well understood.

Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinases (RTKs) subfamily named HER/ERBB that is aberrantly expressed in 80 to 100% of the OSCC cases (9–11). EGFR antagonism including antibodies and tyrosine kinase inhibitors (TKIs) are US Food and Drug Administration (FDA) approved to treat many cancers, including OSCC (12–14). Clinical studies report pain relief in patients with neuropathic pain, including those associated with cancer after treatment with EGFR inhibitors (15, 16). Human genetic studies find associations between painful disease conditions and EGFR and its ligands, such as epiregulin, heparin-binding EGF (HB-EGF), and transforming growth factor–α (TGFα) (17–19). In animal models, HB-EGF directly causes dorsal root ganglion (DRG) cell excitation and elicits pain-like behaviors, whereas epiregulin mainly works in conjunction with underlying inflammation or tissue injury to generate pain (17, 19, 20). EGFR has also been implicated in opioid tolerance in human (21) and animal studies (20, 22, 23). Although elegant mechanistic studies suggest that EGFR can activate various pathways—through the ion channel transient receptor potential vanilloid 1 (TRPV1), the kinase cascade phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR), the protease matrix metalloproteinase–9 (MMP-9), or the oncogene KRAS [to tetrahydrobiopterin (BH4)]—to increase pain sensitivities in mice (17, 24), these studies were done at the spinal level of noncancer pain models. It has been shown that EGFR involvement in pain is ligand and disease dependent (17, 25, 26), which warrants the investigation of EGFR signaling both in the setting of oral cancer pain that involves the trigeminal system and in opioid analgesic tolerance.

In this study, we aimed to determine how EGFR signaling contributes to oral cancer pain and opioid tolerance. We found that EGFR activation sensitizes trigeminal ganglion (TG) neurons and enhances glutamate N-methyl-d-aspartate receptor (NMDAR) signaling, resulting in heightened cancer pain and diminished opioid analgesic efficacy. EGFR ligands abundant in the OSCC tumor microenvironment trigger calcium influx, NMDAR phosphorylation, and protein kinase C (PKC) up-regulation in TG neurons. Last, we showed that EGFR activation induces presynaptic and postsynaptic hypersensitivity of NMDARs in the trigeminal nucleus caudalis (TNc) of the brainstem. Together, these findings establish EGFR-mediated NMDAR sensitization as a central mechanism underlying oral cancer pain and opioid tolerance and highlight EGFR as a promising therapeutic target.

Higher Prevalence of Coronary Microvascular Dysfunction in Patients With HFpEF Without Obesity

Advanced psc-based strategies for leukodystrophy therapy👇

✅Pluripotent stem cell (PSC)–based technologies are opening new avenues for the treatment of leukodystrophies by combining cell replacement, gene correction, disease modeling, and drug discovery within a unified framework.

✅One major approach focuses on the development of off-the-shelf PSC-derived neural progenitor cells (NPCs). By precisely editing immune-related genes, PSCs can be engineered to evade immune rejection. Strategies include knocking out core components of HLA class I and II pathways while introducing protective molecules such as HLA-E, or selectively removing highly immunogenic HLA alleles. These modifications allow the generation of universal donor NPCs that are resistant to T cell– and NK cell–mediated killing.

✅Autologous induced pluripotent stem cell (iPSC) therapy represents a personalized treatment strategy. Patient-derived somatic cells are reprogrammed into iPSCs, followed by genetic correction of disease-causing mutations using viral vectors or CRISPR/Cas9-based editing. Corrected iPSCs are then differentiated into neural stem cells (NSCs), NPCs, or oligodendrocyte progenitor cells (OPCs) and transplanted back into the same patient, minimizing immune complications.

✅Beyond therapy, iPSC-based disease models provide powerful tools to study leukodystrophy pathogenesis. Disease-specific iPSCs recapitulate key cellular phenotypes such as impaired differentiation, lysosomal dysfunction, oxidative stress, and apoptosis. These models enable direct investigation of early developmental defects that are difficult to access in patients.

✅Corrected iPSCs restore normal cellular phenotypes, allowing direct comparison between diseased and healthy isogenic cells. This approach clarifies causal mechanisms and validates gene correction strategies at the cellular level, supporting precision medicine.

✅iPSC-derived neural systems also support advanced drug discovery platforms. By generating complex neural cultures or myelinating organoids (“myelinoids”), researchers can model neuron–glia interactions and myelination in vitro. Coupled with immunofluorescence, transcriptomics, and high-throughput screening, these systems enable systematic identification of small molecules that promote myelination or correct metabolic defects.

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Scientists discover how to reactivate cancer’s molecular “kill switch”

(Farmington, Conn. – March 13, 2025) – Alternative RNA splicing is like a movie editor cutting and rearranging scenes from the same footage to create different versions of a film. By selecting which scenes to keep and which to leave out, the editor can produce a drama, a comedy, or even a thriller—all from the same raw material. Similarly, cells splice RNA in different ways to produce a variety of proteins from a single gene, fine-tuning their function based on need. However, when cancer rewrites the script, this process goes awry, fueling tumor growth and survival.

In a recent study reported in the Feb. 15 issue of Nature Communications, scientists from The Jackson Laboratory (JAX) and UConn Health not only show how cancer hijacks this tightly regulated splicing and rearranging of RNA but also introduce a potential therapeutic strategy that could slow or even shrink aggressive and hard-to-treat tumors. This discovery could transform how we treat aggressive cancers like triple-negative breast cancer and certain brain tumors, where current treatment options are limited.

At the heart of this work, led by Olga Anczuków, an associate professor at JAX and co-program leader at the NCI-designated JAX Cancer Center, are tiny genetic elements called poison exons, nature’s own “off switch” for protein production. When these exons are included in an RNA message, they trigger its destruction before a protein can be made—preventing harmful cellular activity. In healthy cells, poison exons regulate the levels of key proteins, keeping the genetic machinery in check. But in cancer, this safety mechanism often fails.

Genetic identification of mouse trigeminal afferents responsible for mechanical allodynia

Peripheral mechanisms by which the nerve afferents send signals after nerve injury in mechanical C is not well understood.

The researchers identify a subset of trigeminal afferents in mice activated by facial brushing after nerve injury. Many of brushing-activated (BA) trigeminal ganglia (TG) neurons express neurofilament200 and Ntrk3, markers for low-threshold mechanoreceptors, with lower co-localization with nociceptor markers such as Calca or Trpv1.

Inhibition of BA TG neurons reduces mechanical allodynia, while their activation increases spontaneous face wiping after nerve injury.

Knockdown of Piezo2 from BA TG afferents reduces mechanical allodynia. Thus, targeted manipulations reveal these neurons’ causal role in pain-like behaviors and heightened sensitivity, providing new insights into primary afferents underlying mechanical allodynia. sciencenewshighlights ScienceMission https://sciencemission.com/trigeminal-afferents

Peripheral mechanisms of mechanical allodynia after nerve injury remain unclear. Li et al. identify a subset of trigeminal afferents in mice activated by facial brushing after nerve injury. Targeted manipulations reveal these neurons’ causal role in pain-like behaviors and heightened sensitivity, providing new insights into primary afferents underlying mechanical allodynia.

Uncovering genetic interactions in the DNA repair network in response to endogenous damage and ionizing radiation

Nebenfuehr et al. perform a combinatorial CRISPR-Cas9 screen targeting 461 DNA damage response genes under basal and irradiated conditions. The study maps thousands of genetic interactions, generating a rich resource to uncover mechanisms of genome maintenance and inspire future studies.

Dr. Chris Oswald — Precision Nutrition, Epigenetics & Practitioner-Led Longevity Care

Precision Nutrition, Epigenetics & Practitioner-Led Longevity Care — Dr. Chris Oswald — Head of Medical Affairs, Pure Encapsulations, Nestlé Health Science.

Dr. Chris Oswald, DC, CNS, is Head of Medical Affairs for Pure Encapsulations (https://www.pureencapsulations.com/), part of Nestlé Health Science family. He is a chiropractor, certified nutrition specialist and certified functional medicine practitioner and has been treating patients since 2007.

At Pure Encapsulations, Dr. Oswald leads medical education, scientific strategy, and innovation across well-known professional brands including Pure Encapsulations, Douglas Labs, Klean Athlete, Genestra, and others. In this role, he sits at the intersection of clinical science, practitioner education, and product innovation — translating complex evidence into practical tools that help healthcare professionals practice more confident, personalized nutritional medicine.

Dr. Oswald’s clinical work, in combination with his work in professional dietary supplement companies, gives him unique insight into the creation of clinically useful tools and education to support the unique needs of clinicians and patients in functional, integrative and natural health.

Before joining Pure Encapsulations, Dr. Oswald held senior leadership roles across the nutraceutical and health tech landscape, including Chief Science Officer, Head of Product Innovation and R&D, Head of Operations, Interim Head of Sales, and VP of Nutraceuticals at companies like January AI and Further Food. Across those roles, he’s led everything from supply chain and regulatory strategy to product development, claims substantiation, and national practitioner education.

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New study reveals how stress alters brain gene activity through RNA “switches”

The study, published in Genomic Psychiatry, identified how stress hormones activate specific RNA molecules called long noncoding RNAs, or IncRNAs, that interact with the gene-silencing complex PRC2, turning off genes that are vital to communication between neurons. In essence, these IncRNAs act like “switches,” turning off functionality for more than 3,000 genes, many of which support neurotransmitter signaling and other processes that are essential for healthy brain functioning. The study specifically discovered 79 IncRNAs that were significantly altered under stress conditions.

While scientists have long understood that stress hormones send signals to the brain that affect gene functionality, it was previously unknown as to exactly how these signals create long-lasting changes inside cells. The study, led by Yogesh Dwivedi, Ph.D., Distinguished Professor and Elesabeth Ridgely Shook Endowed Chair in the Department of Psychiatry and Behavioral Neurobiology, and co-director of UAB Depression and Suicide Center, uncovers how lncRNAs associate with a molecule called polycomb repressive complex 2, or PRC2, to modify chromatin following activation of the glucocorticoid receptor, or GR — the cell’s master regulator of stress response. Chromatin is important in relaying messages from the external environment, including stressful conditions, to alter the genetic composition, a process known as epigenetics.

“As chronic stress is a major risk factor for conditions like major depressive disorder, this newly uncovered link between stress hormones and IncRNA gene silencing could potentially lead to more targeted mental health treatments,” Dwivedi said. “In fact, stress-induced changes in chromatin structure have been implicated in a range of psychiatric and neurodegenerative conditions.”

IncRNAs act like “switches,” turning off functionality for more than 3,000 genes that are essential for healthy brain functioning. A recent groundbreaking study from researchers at the University of Alabama at Birmingham highlights the discovery of a molecular link between stress hormones and changes in brain cell communication, which could open the door for new treatments to address depression and other psychiatric conditions.

A world-first mouse that makes gene activity visible

DNA can be thought of as a vast library that stores all genetic information. Cells do not use this information all at once. Instead, they copy only the necessary parts into RNA, which is then used to produce proteins—the essential building blocks of life. This copying process is called transcription, and it is carried out by a molecule known as RNA polymerase II.

When RNA polymerase II begins actively transcribing DNA, a specific site called Ser2 on its tail region is marked with a small chemical group known as a phosphate. This phosphate acts as a sign that transcription is in progress. Until now, observing this sign required stopping cellular activity and chemically treating the cells to visualize the phosphate. As a result, it was impossible to see how transcription changes dynamically in living cells.

To overcome this limitation, a research team led by Professor Hiroshi Kimura at Institute of Science Tokyo (Science Tokyo) chose a different approach. Instead of freezing cells at a single moment, they aimed to track transcription continuously without stopping cellular activity.

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